The objective of the proposed studies is to design and test new immunotherapeutic modalities for the treatment of human bladder cancer. Intravesical administration of Bacillus Calmette Guerin (BCG) for superficial transitional cell carcinoma (TCC) of the bladder has proven the most effective anti-tumor immunotherapy to date, however, its mechanism of action has yet to be determined. Although BCG significantly extends the tumor free period, more than half of those treated recur within the first 2 years. The studies described in this application are designed to characterize the localized immunologic response to BCG in bladder and, based on the results, identify and test agents which can be used to enhance the effectiveness of BCG. The long term goal of these studies is to develop treatment schemes which can be used in clinical trials for human bladder carcinoma. The approach which we have selected utilizes a well established murine model for human TCC in which tumor progression and responsiveness to BCG models the human disease. We will first characterize the host response towards the intravesical growth of the MBT-2 tumor at the cellular level, placing particular emphasis on the anti-tumor lytic and tumor responsive lymphokine producing cells found to infiltrate the tumor (Aim I). In addition to identifying these tumor infiltrating lymphocytes (TIL), we will examine the mechanism of the host response in studies which will include in-vivo depletion of subpopulations of host lymphocytes. The role of tumor necrosis factor (TNF) in host resistance will be ascertained by in-vivo neutralization using anti-TNF antibodies. Following this initial characterization, in Aim II, we will determine the effects of intravesical BCG on the host anti-tumor response in order to determine its mechanism of action (ie. what changes in immune parameters at the tumor site are associated with its anti-tumor effect). While these studies characterize an already successful therapeutic, they will form an essential basis for the identification of agents and treatment schemes which will enhance the efficacy of BCG. Based on the results of these studies, we will be able to predict and test additional agents (lymphokines, cytokines, and immune-modulating drugs) which will enhance BCG's actions (Aim III).